Dr. Michael Newberg received his M.D. and Ph.D. from the University of Virginia, and did his thesis research on CD8+ T lymphocyte recognition of MHC class I molecules. He completed internal medicine residency training at the University of Virginia, and infectious disease fellowship training at Beth Israel Deaconess Medical Center. He has spent three years in the laboratory of Dr. Norman Letvin, studying epitope-specific CTL responses in SIV/SHIV-infected rhesus monkeys as a model for HIV-1 infection, and in assessing HIV-1 vaccine strategies. His immediate goals are to continue his research, while acquiring additional training in virology and molecular immunology, and developing as an independent investigator. Toward this goal, he plans to enroll in several graduate-level courses (Animal Virology; HIV Molecular Biology; Molecular Biology Techniques; and Molecular Immunology); attend weekly seminars, case conferences, lab meetings and journal clubs; and meet regularly with his mentor, Dr. Letvin, and an oversight committee of senior investigators. Dr. Newberg's long-term career goals are to become an independent investigator, conducting clinically relevant research in cellular immunology, as well as seeing patients. The research project described in this proposal is intended to address unresolved issues regarding SIV/SHIV epitope-specific CTL responses as a model for HIV-1 epitope-specific CTL responses in infected individuals. Initially, Dr. Newberg will complete the characterization of Mamu-A*02-restricted SIV/SHIV epitope-specific CTL in rhesus monkeys. He will then assess the development of Mamu-A*02-restricted epitope-specific CTL responses in SIV-infected Mamu-A*01+ Mamu-A*02+ rhesus monkeys, to determine whether the presence of the immunodominant Mamu-A*01/Gag p11C-specific CTL response resulted in the suppression of subdominant CTL responses. He will also sequence the regions of SIV encoding the Mamu-A*02-restricted CTL epitopes that are isolated from infected Mamu-A*02+ rhesus monkeys at various time points, in order to determine the clinical consequences of viral escape from SIV-specific CTL that are specific for epitopes that are not overwhelmingly dominant. Finally, he will evaluate the Vbeta repertoires, CDR3 length spectratypes, and TCR beta sequences of Mamu-A*02-restricted epitope-specific CTL, to characterize the degree of clonal diversity of CTL responses specific for SIV epitopes that are nondominant.